1-Substituted-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine

ABSTRACT

Piperidines of the formula ##STR1## in which R 1  stands for optionally substituted aryl, R 2  for hydrogen, lower alkyl, lower alkenyl, acyl or α-aryl-lower alkyl, R 3  for a free or substituted hydroxyl group, alk for lower alkylene which separates the two nitrogen atoms by 2 or 3 carbon atoms, R 4  represents hydrogen or lower alkyl and n represents an integer from 1 to 4, and their salts as well as processes for their manufacture and pharmaceutical compositions comprising such compounds, and a process for lowering the blood pressure wherein such compositions are administered to a warm-blooded host.

CROSS REFERENCE TO OTHER APPLICATIONS

This is a division of copending application Ser. No. 483,742 filed JUne27, 1974, now U.S. Pat. No. 3,956,335, which, in turn, is a continuationin part of our copending application Ser. No. 389,106, filed Aug. 16,1973, now abandoned.

SUMMARY OF THE INVENTION

The invention relates to new piperidines of the formula I ##STR2##wherein R₁ represents an optionally substituted aryl radical, R₂represents hydrogen, lower alkyl, lower alkenyl, acyl or α-aryl-loweralkyl, R₃ represents a free or substituted hydroxyl group, alkrepresents a lower alkylene radical which separates the two nitrogenatoms by 2 or 3 carbon atoms, R₄ represents hydrogen or lower alkyl andn represents 1 to 4, and their salts, as well as processes for theirmanufacture and pharmaceutical compositions comprising such compounds aswell as a process for lowering the blood pressure (for treatinghypertension) and/or treating tachycardia characterised in that suchcompositions are administered to a mammal.

An optionally substituted aryl radical R₁ is, for example, amonosubstituted, disubstituted or polysubstituted phenyl or naphthylradical or an unsubstituted phenyl or naphthyl radical and also, forexample, an optionally substituted 5,6,7,8-tetrahydro-1-naphthyl radicalor 2-naphthyl radical. A monosubstituted or disubstituted phenyl ornaphthyl radical and especially a monosubstituted phenyl radical ornaphthyl radical and very particularly a monosubstituted phenyl radical,are preferred.

The aryl radical R₁ is substituted, for example, by aliphatichydrocarbon radicals, especially by lower aliphatic hydrocarbon radicalswhich can also be substituted. Examples of such optionally substitutedlower aliphatic hydrocarbon radicals are lower alkyl groups, loweralkenyl groups, lower alkynyl groups, lower alkoxy-lower alkyl groups,lower alkylthio-lower alkyl groups, hydroxy-lower alkyl groups,halogeno-lower alkyl groups, lower alkoxycarbonylamino-lower alkylgroups and acylamino-ethenyl groups.

A substituent of an aryl radical R₁ can also be hydroxyl which isoptionally etherified by an aliphatic hydrocarbon radical, especially bya lower aliphatic hydrocarbon radical, which can be substituted yetfurther. Examples of such radicals are lower alkoxy groups, loweralkenyloxy groups, lower alkynyloxy groups, lower alkoxy-lower alkoxygroups, lower alkylthio-lower alkoxy groups, aryl-lower alkoxy groups,such as phenyl-lower alkoxy groups, for example benzyloxy groups, andhydroxyl groups.

The aryl radical R₁ can also be optionally substituted by the followingsubstituents: Alkanoyl groups, alkanoyloxy groups, lower alkylthiogroups, acylamino groups, hydrogen atoms or cyano, amino and/or nitrogroups.

Further substituents of the aryl radical R₁ are optionally substitutedcarbamoyl groups, such as, for example, N-lower alkylcarbamoyl groups,N,N-di-lower alkylcarbamoyl groups or N,N-lower alkylenecarbamoylgroups.

An optionally substituted ureido group can also be a substituent of thearyl radical R₁.

Particularly suitable substituents of the aryl radical R₁ are optionallysubstituted carbamoyl groups, lower alkoxycarbonylamino-lower alkylgroups, lower alkoxy-lower alkoxy groups, acylamino-ethenyl groups,lower alkylthio-lower alkoxy groups, the hydroxyl group and alkanoylgroups, nitrile groups and especially acylamino groups and veryparticularly lower alkoxy groups, lower alkenyl groups, lower alkenyloxygroups and halogen atoms.

Lower radicals in the preceeding and following text are above allradicals which contain up to 7 C atoms, in particular up to 4 C atoms.

Lower alkyl radicals are, for example, methyl, ethyl, n-propyl orisopropyl, or straight-chain or branched butyl, pentyl or hexyl, whichcan be bonded in any desired position.

Lower alkoxy radicals are, in particular, radicals which preferably haveup to 7 C atoms in the lower alkyl part, especially up to 4 C atoms,with lower alkyl having the above meaning. Examples of such lower alkoxyradicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy andn-amyloxy. Two lower alkoxy radicals, especially two adjacent loweralkoxy radicals, can also be linked, as lower alkylenedioxy, for examplemethylenedioxy.

Examples of lower alkenyl radicals are vinyl, propenyl, allyl ormethallyl. Examples of lower alkenyloxy radicals are allyloxy,methallyloxy or propenyloxy.

Examples of lower alkoxy-lower alkyl radicals are those which have up to7 C atoms, preferably up to 4 C atoms, in each lower alkyl part, forexample methoxymethyl, ethoxymethyl, n-proproxymethyl, n-butoxymethyl,2-(n-butoxy)-ethyl, 3-(n-propoxy)-propyl or particularly 2-methoxyethyl.

Examples of lower alkoxy-lower alkoxy radicals are those which containup to 7 C atoms, preferably up to 4 C atoms, in each lower alkyl part,with the lower alkyl part having the above meaning. Examples of suchradicals are, for instance, methoxy-methoxy, ethoxymethoxy,1-methoxyethoxy, 4-methoxy-n-butoxy, 3-methoxy-n-butoxy and especially3-methoxy-n-propoxy, 2-methoxyethoxy and 2-ethoxyethoxy.

Lower alkinyl radicals are in particular propargyl radicals; loweralkinyloxy radicals are, in particular, propargyloxy radicals.

As alkanoyl radicals there should above all be mentioned lower alkanoylradicals, such as propionyl or butyryl radicals, but above all theacetyl radical; examples of alkanoyloxy radicals are those in which thealkanoyl part has the above meaning.

Examples of lower alkylmercapto groups are groups in which the loweralkyl part is defined as above. Examples of such groups areethylmercapto, isopropylmercapto, n-butylmercapto and especiallymethylmercapto.

Lower alkylthio-lower alkyl groups have, for example, up to 7 C atoms,preferably up to 4 C atoms, in each lower alkyl part and are thus, forexample, methylthiomethyl, 2-ethylthioethyl, 3-methylthio-n-propyl andespecially 2-methylthioethyl.

Lower alkylthio-lower alkoxy groups are, for example, groups whichpossess up to 7 C atoms, preferably up to 4 C atoms, in each lower alkylpart. Examples of such groups are methylthiomethoxy, 2-ethylthioethoxy,3-methylthio-n-propoxy and especially 2-methylthioethoxy.

Hydroxy-lower alkyl groups are above all those with at most 7 C atoms,preferably with at most 4 C atoms, in which the lower alkyl part has theabove meaning, such as, for example, 2-hydroxyethyl, 3-hydroxy-n-propyland especially hydroxymethyl.

Possible halogen atoms are in particular fluorine atoms or bromine atomsand especially chlorine; examples of halogeno-lower alkyl groups aregroups in which the lower alkyl part has the above meaning, for examplechloromethyl, 2-chloroethyl, dichloromethyl and especiallytrifluoromethyl.

N-lower alkylcarbamoyl groups contain, as the lower alkyl part, inparticular the radicals singled out above. N,N-Di-lower alkylcarbamoylgroups for example contain the radicals described above as the loweralkyl part. N,N-Lower alkylenecarbamoyl in particular contains, as thelower alkylene part, butylene-1,4 or pentylene-1,5. Examples of suchradicals are N-methylcarbamoyl, N,N-dimethylcarbamoyl,pyrrolidino-carbonyl and piperidino-carbonyl.

An optionally substituted ureido group is a group in which the freeamino group can optionally be substituted by lower alkyl groups, withlower alkyl having the above meaning, such as, for example, aN',N'-dimethylureido group or N',N'-diethylureido group. If the ureidogroup is substituted by divalent radicals, these radicals, which canoptionally be interrupted and/or substituted by hetero-atoms, arepreferably lower alkylene radicals which can be straight-chain orbranched and above all possess 4-6 chain carbon atoms if the carbonchain is uninterrupted or 4 or 5 carbon atoms if the carbon chain isinterrupted by hetero-atoms. Possible hetero-atoms are, in particular,oxygen, sulphur and nitrogen. Examples of such radicals arebutylene-(1,4), pentylene-(1,5), hexylene-(1,5), hexylene-(2,5),hexylene-(1,6), heptylene-(1,6), 3-oxapentylene-(1,5),3-oxahexylene-(1,6), 3-thia-pentylene-(1,5),2,4-dimethyl-3-thia-pentylene-(1,5), 3-aza-pentylene-(1,5) and 3-loweralkyl 3-aza-pentylene-(1,5), such as 3-methyl-3-azapentylene-(1,5) or3-aza-hexylene-(1,6). N'-Lower alkylureido, such as N'-methylureido, andthe above N', N'-di-lower alkylureido are also suitable as ureido.

By lower alkoxycarbonylamino-lower alkyl groups there are understoodradicals of which the lower alkyl part possesses, for example, up to 7 Catoms, preferably up to 4 C atoms, both in the lower alkoxy part and inthe lower alkyl part itself. Examples of such groups aremethoxycarbonylaminomethyl, ethoxycarbonylaminomethyl,4-methoxycarbonylamino-n-butyl, 2-ethoxycarbonylaminoethyl,3-ethoxycarbonylamino-n-propyl and particularly2-methoxycarbonylamino-ethyl and 3-methoxycarbonyl-n-propyl.

Acylamino groups are especially those which contain cycloaliphatic,aromatic, araliphatic and above all aliphatic acyl radicals as acylradicals.

Aliphatic acyl radicals of the formula R--CO-- are especially those inwhich R is a lower alkyl radical. Examples of lower alkyl radicals arethose with at most 7 C atoms, such as the methyl, ethyl, iso- andn-propyl radical and straight and branched butyl, pentyl and hexylradicals bonded in any desired position.

Cycloaliphatic acyl radicals of the formula R'--CO-- are especiallythose in which R' denotes an optionally loweralkylated lower cycloalkylradical, above all with 3-7, in particular 5-7, ring members, such as,for example, the cyclopropyl, cyclopentyl, cyclohexyl and cycloheptylradical.

Benzoyl and naphthoyl radicals, or phenyl-lower alkanoyl radicals, suchas phenylacetyl or α- and β-phenylpropionyl radicals, may be mentionedas examples of aromatic or araliphatic acyl radicals, respectively.

The acyl radicals mentioned can be substituted yet further.

The following may be mentioned as examples of substituents of thearomatic and araliphatic acyl radicals, with the substituents preferablybeing located on the rings: Lower alkyl radicals, such as thosementioned above, halogen atoms, such as fluorine, bromine and iodine andespecially chlorine, the pseudo-halogen trifluoromethyl, and loweralkoxy groups. One, two or more such substituents can be present.

Preferred acyl radicals are benzoyl and especially acetyl.

Acylamino-ethylene groups are in particular radicals of the formula##STR3## wherein R₅ is a lower alkyl group having the above meaning, alower alkoxy group having the above meaning or an amino group, that isto say a primary, secondary or tertiary amino group, preferably loweralkylamino or di-lower alkylamino, with the lower alkyl part in eachcase having the above meaning; R₆ is hydrogen or a lower alkyl grouphaving the above meaning; R₇ is hydrogen, a lower alkyl group having theabove meaning, carboxyl or lower alkoxycarbonyl, in which the loweralkoxy part has the above meaning; R₈ is hydrogen or a lower alkyl grouphaving the above meaning.

Lower alkyl or lower alkenyl groups R₂ are in particular the lower alkylor lower alkenyl groups indicated above and defined in more detail assubstituents of the aryl radical R₁. Examples of acyl radicals R₂ areradicals of which the acyl part in particular has the meaning indicatedabove for acylamino groups, above all a lower alkanoyl radical, such asan acetyl group or aroyl, for example optionally substituted benzoyl,suitable substituents being, for example, lower alkyl, lower alkoxy,halogen and/or trifluoromethyl, and the benzoyl radical in particularrequiring to be singled out.

An α-aryl-lower alkyl radical is, for example, an optionally substitutedphenylalkyl or naphthylalkyl radical or an optionally substituted5,6,7,8-tetrahydro-1- or -2-naphthylalkyl radical. An optionallysubstituted phenyl-lower alkyl radical, and very particularly the benzylradical, is preferred. Suitable substituents of the aryl part of theα-aryl-lower alkyl radical are above all lower alkyl radicals, halogenatoms or the substituents indicated under the definition of R₁ beingaryl.

A substituted hydroxyl group R₃ is, for example, an etherified hydroxylgroup or, preferably, an esterified hydroxyl group.

By an etherified hydroxyl group there is above all understood a hydroxylgroup etherified by a lower alkyl group, in which the lower alkyl parthas the above meaning. Examples of such radicals are n-propoxy, ethoxyand especially methoxy groups.

An esterified hydroxyl group is, for example, an acyloxy group of whichthe acyl part in particular has the meaning indicated above foracylamino groups. Particular interest attaches to hydroxyl groupsesterified by aliphatic acyl radicals of the formula R--CO--, in which Rin particular is a lower alkyl radical, that is to say lower alkanoyloxyradicals. Examples of such radicals are propionyloxy, butyryloxy andespecially acetoxy.

Lower alkyl groups R₄ are, in particular, the above mentioned radicals,for example ethyl, n-propyl, isopropyl and especially methyl.

A lower alkylene radical alk is, in particular, a straight or branchedlower alkylene radical which possesses 2 or 3 chain carbon atoms but canin total contain up to, for example, 7, especially 4, C atoms.Preferably, alk is an optionally lower-alkylated dimethylene ortrimethylene radical, especially a dimethylene or trimethylene radicalwhich is optionally monosubstituted by lower alkyl which has the abovemeaning, and very particularly an unsubstituted dimethylene ortrimethylene radical.

The new compounds possess valuable pharmacological properties. Thus theyshow a blood pressure-lowering action, as can be shown in animalexperiments, for example on intravenous administration of doses of about1-100 mg/kg to narcotised cats. In addition, the new compounds producean antitachycardia and α-sympathicolysis as can again be shown in animalexperiments, for example in experiments carried out in vitro atconcentrations of 3-100 γ/ml on guinea-pigs (Langendorff preparation) orin vitro experiments at concentrations of 0.1 to 100 γ/ml on rats(isolated perfused mesenterial artery). The new compounds are thereforeuseful as anti-hypertensive agents, antitachycardia agents andα-sympathicolytic agents. The new piperidines can furthermore serve asstarting products or intermediate products for the manufacture of other,especially of therapeutically active, compounds.

Compounds to be particularly mentioned are compounds of the formula I,wherein R₁ is a phenyl radical which is optionally substituted in thep-, m- and/or preferably o-position, R₂ is hydrogen, lower alkyl, loweralkenyl, acyl or benzyl, R₃ is a free, etherified or esterified hydroxylgroup, R₄ is hydrogen or lower alkyl and n is 1- 4 and alk is anoptionally loweralkylated-dimethylene or trimethylene radical.

Further compounds to be singled out are compounds of the formula I,wherein R₁ is a phenyl radical which is monosubstituted or disubstitutedby lower alkyl, lower alkoxy, lower alkenyl, lower alkenyloxy, halogen,halogeno-lower alkyl, carbamoyl which is optionally substituted by loweralkyl groups, lower alkoxycarbonylamino-lower alkyl, lower alkoxy-loweralkoxy, acylamino-ethenyl, lower alkylthio-lower alkoxy, hydroxyl, loweralkanoyl, lower alkoxyalkyl, lower alkinyl, lower alkylthio-lower alkyl,hydroxy-lower alkyl, lower alkanoyloxy, lower alkylthio, acylamino,nitrile, amino, nitro, optionally substituted ureido and/or loweralkinyloxy, R₂ is hydrogen, lower alkyl, lower alkenyl or loweralkanoyl, R₃ is a free hydroxyl group, a lower alkanoyloxy group or alower alkoxy group and R₄ is hydrogen or lower alkyl, with n being 1 andalk being an optionally mono-lower alkylated dimethylene or trimethyleneradical. Furthermore, R₁ can also be unsubstituted phenyl or naphthyland the other substituents can have the meanings indicated for the groupof compounds Id.

Compounds to be singled out very particularly are compounds Id of theformula I, wherein R₁ is phenyl which is monosubstituted by lower alkyl,lower alkoxy, lower alkenyl, lower alkenyloxy, halogen, optionally loweralkyl-substituted carbamoyl, lower alkoxycarbonylamino-lower alkyl,lower alkoxy-lower alkoxy, lower alkanoylaminoethenyl, loweralkylthio-lower alkoxy, hydroxyl or lower alkanoyl, R₂ is hydrogen,lower alkyl, lower alkenyl or lower alkanoyl, R₃ is free hydroxyl orlower alkanoyloxy, R₄ is hydrogen or lower alkyl, with n=1, and alk isan optionally mono-lower alkylated ethylene or trimethylene radical.

Compounds to be mentioned very particularly are compounds of the formulaI, wherein R₁ is a phenyl radical which is monosubstituted by loweralkyl, lower alkoxy, lower alkenyl, lower alkenyloxy, lower alkanoyl,lower alkanoylamino, hydroxyl, N-lower alkyl-carbamoyl or halogen, R₂ ishydrogen or lower alkyl, R₃ is hydroxyl, R₄ is hydrogen and alk is anoptionally monomethylated ethylene or trimethylene radical.

Compounds to be singled out very particularly are piperidines of theformula I, wherein R₁ is phenyl monosubstituted by methyl, methoxy,allyl, allyloxy, hydroxyl, acetylamino, propionyl, N-methyl-carbamoyl,or chlorine, R₂ is hydrogen or methyl, R₃ is hydroxyl, R₄ is hydrogenand alk is ethylene or trimethylene.

Especially valuable are the compounds of the formula ##STR4## in whichR' stands for halogen, lower alkyl or lower alkoxy, especially forchlorine or particularly for methyl or methoxy, R" for lower alkyl, suchas ethyl or especially methyl, or particularly hydrogen, R'" for methylor especially hydrogen and alk' for ethylene or trimethylene and aboveall 1-[3-(o-chloro-phenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidine,1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(3-methyl-2-oxo-1-imidazolidinyl)-piperidine,1-[3-(o-chlorophenoxy)-2-hydroxy-propyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidineor particularly1-[3-(o-methylphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,1[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, 1-[3 -(o-methylphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidine and especially1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidine, which in renal hypertonic dogs ina dose of 50 mg/kg p.o. shows a significant antihypertensive action,coupled with good toleration.

The new compounds are obtained according to methods which are inthemselves known.

For example, it is possible to react a compound of the formula IIa##STR5## with a compound of the formula IIIa ##STR6## wherein R₁, R₂,R₄, n and alk have the above meaning and either X represents a free orsubstituted hydroxyl group R₃, and Z represents a reactive esterifiedhydroxyl group or X and Z together form an epoxy group.

A reactive, esterified hydroxyl group is in particular a hydroxyl groupesterified by a strong inorganic or organic acid, above all a hydrohalicacid, such as hydrochloric acid, hydrobromic acid or hydriodic acid, oran organic sulfonic acid, such as an aromatic sulfonic acid, for examplebenzenesulphonic acid, p-bromobenzenesulphonic acid orp-toluenesulphonic acid. Thus Z in particular represents chlorine,bromine or iodine.

The reaction is carried out in the usual manner. If a reactive ester isused as the starting material, the reaction is preferably carried out inthe presence of a basic condensation agent and/or with an excess of thecompound of the formula IIIa.

In resulting compounds, substituents can be split off, introduced ormodified within the framework of the end products.

Thus it is possible, in a resulting compound of the formula I, whereinR₁ is an aryl radical substituted by a functionally modified carboxylgroup and the other substituents have the above meaning, to convert thisradical into an aryl radical substituted by a carbamoyl group, N-loweralkylcarbamoyl group, N,N-di-lower alkylcarbamoyl group or N,N-loweralkylenecarbamoyl group, for example by reaction with an optionallyN-mono- or N-di-alkyl substituted amine or N,N-loweralkylene-substituted amine.

An optionally functionally modified carboxyl group is above all acarboxyl group esterified with an alcohol or phenol. Examples ofsuitable alcohols are lower alkanols, such as ethanol of methanol.Examples of suitable phenols are phenol or p-nitrophenol.

The reaction is carried out in the usual manner, especially at anelevated temperature, and if appropriate at a drastically elevatedtemperature, such as up to more than 200° C, under pressure if desired,and with an excess of the particular amine if desired. If the reactionis carried out at room temperature or only moderately elevatedtemperature, it is preferably carried out in an inert solvent, allowinga longer reaction time. Examples of inert solvents are alcohols, such asmethanol or ethanol, ethers, such as diethyl ether or dioxane, benzeneand the like.

Furthermore it is possible, in resulting compounds of the formula I,wherein R₂, R₃, R₄, n and alk have the above meaning and R₁ is an arylradical substituted by a hydroxyl group, to convert this radical R₁either into an aryl radical substituted by lower alkoxy-lower alkoxy,for example by reaction with a compound of the formula loweralkoxy-lower alkyl-Z.sub. 1, wherein Z₁ is a reactive esterifiedhydroxyl group, or to convert R₁ into an aryl radical substituted by alower alkoxy group, for example by reaction with a compound of theformula lower alkyl-Z₁, wherein Z₁ is a reactive esterified hydroxylgroup, or to convert R₁ into an aryl radical substituted by a loweralkenyloxy group, such as, for example, by reaction with a compound ofthe formula alkenyl-Z₁, wherein Z₁ is a reactive esterified hydroxylgroup. The reactants can in particular be used in the form of theirsalts.

In resulting compounds in which R₂ is hydrogen, the latte can bereplaced in the usual manner by a lower alkyl or lower alkenyl radical,especially in accordance with the processes described above, by reactinga compound of the formula I, wherein R₁, R₃, R₄, n and alk have theabove meaning and R₂ is hydrogen, with a compound of the formula loweralkyl-(lower alkenyl)-Z, wherein Z is a reactive esterified hydroxylgroup.

The reactions mentioned can optionally be carried out simultaneously orsuccessively and in optional sequence.

The reactions mentioned are carried out in the usual manner in thepresence or absence of diluents, condensation agents and/or catalyticagent, at lowered, ordinary or elevated temperature, and in a closedvessel if desired.

Depending on the process conditions and starting substances, the endproducts are obtained in the free form or in the form of their acidaddition salts which is also included in the invention. Thus, forexample, basic, neutral or mixed salts and optionally also hemihydrates,monohydrates, sesquihydrates or polyhydrates thereof, can be obtained.The acid addition salts of the new compounds can be converted into thefree compound in a manner which is in itself known, for example withbasic agents, such as alkalis or ion exchangers. On the other hand, thefree bases obtained can form salts with organic or inorganic acids. Tomanufacture acid addition salts, those acids are in particular usedwhich are suitable for forming therapeutically usable salts. As examplesof such acids there may be mentioned: Hydrogen halide acids, for examplehydrochloric acid, sulphuric acids, for example sulphuric acid,phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic,aromatic or heterocyclic carboxylic acids or sulphonic acids, such asformic acid, acetic acid, propionic acid, succinic acid, glycollic acid,lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid,maleic acid, hydroxymaleic acid or pyruvic acid, fumaric acid, benzoicacid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid,salicylic acid or P-aminosalicyclic acid, embonic acid, methanesulphonicacid, ethanesulphonic acid, hydroxyethanesulphonic acid,ethylenesulphonic acid, halogenobenzenesulphonic acids, toluenesulphonicacid, naphthalenesulphonic acid or sulphanilic acid, methionine,tryptophane, lysine or arginine.

These or other salts of the new compounds, such as, for example, thepicrates, can also be used for purifying the resulting free bases, byconverting the free bases into salts, isolating these and againliberating the bases from the salts. Because of the close relationshipsbetween the new compounds in the free form and in the form of theirsalts, the free compounds are to be understood, in the preceding andfollowing text, where appropriate also to include the correspondingsalts, with regard to general sense and intended use.

The invention also relates to those embodiments of the process accordingto which a compound obtainable as in intermediate product at any stageof the process is used as the starting compound and the missing processsteps are carried out, or the process is stopped at any stage, or inwhich a starting substance is formed under the reaction conditions or inwhich a reactant is present in the form of its salts, if appropriate.

The new compounds can, depending on the choice of the startingsubstances and procedures, be in the form of optical antipodes orracemates or, if they contain at least two asymmetrical carbon atoms,also racemate mixtures and/or pure geometrical isomers or mixturesthereof (isomer mixtures).

Isomer mixtures obtained can be separated, on the basis of thephysico-chemical differences of the constituents, in a known manner intothe two pure geometrical isomers, for example by chromatography on asuitable stationary phase, such as silica gel or aluminium oxide whichhave been pretreated with a complex-forming heavy metal compound, forexample with a silver compound, or by forming a heavy metal additioncompound, for example the silver nitrate complex, separating the latterinto the addition compounds of the pure isomers, for example byfractional crystallisation, and subsequently liberating the pureisomers.

Resulting pure isomers, for example trans-isomers, can be converted inthe usual manner, for example photochemically, for example byirradiation with light of a suitable wavelength, advantageously in asuitable solvent, such as an aliphatic hydrocarbon, or in the presenceof a suitable catalyst, into the particular isomers of oppositeconfiguration, for example into the cis-isomers.

Racemate mixtures can be separated in a known manner, on the basis ofthe physico-chemical differences of the constituents, into the twostereroisomeric (diastereomeric) pure racemates, for example bychromatography and/or fractional crystallisation.

Resulting racemates can be resolved according to known methods, forexample by recrystallisation from an optically active solvent, with theaid of micro-organisms or by reaction with an optically active acidwhich forms salts with the racemic compounds and separation of the saltsobtained in this manner, for example on the basis of their differentsolubilities, into the diastereomers, from which the antipodes can beliberated by the action of suitable agents. Particularly customaryoptically active acids are, for example, the D- and L-forms of tartaricacid, di-o-toluyltartaric acid, malic acid, mandelic acid,camphorsulphonic acid or guinic acid. Advantageously, the more activeL-antipode is isolated.

Appropriately, those starting substances are used for carrying out thereactions according to the invention which lead to the initiallyparticularly mentioned groups of end products and especially to the endproducts which have been particularly described or singled out.

A compound of the formula IIIa can be manufactured by hydrogenatingcompounds of the formula VI ##STR7## preferably catalytically asdescribed above.

Compounds of the formula IIIa are new and are used as intermediateproducts for the manufacture of compounds of the formula I and also froma subject of the invention.

The starting compounds are known or can, if they are new, be obtainedaccording to methods which are in themselves known.

The new compounds can be used as medicines, for example in the form ofpharmaceutical compositions, in which they are present in their freeform or in the form of their therapeutically acceptable salts, inadmixture or conjunction with a pharmaceutical, organic or inorganic,solid or liquid excipient which is suitable, for example, for enteral,e.g., oral, or parenteral administration. Possible substances forforming the excipient are those which do not react with the newcompounds, such as, for example, water, gelatine, lactose, starch,magnesium stearate, talc vegetable oils, benzyl alcohols, gum,polyalkylene glycols, white petroleum jelly, cholesterol or other knownmedicinal excipients. The pharmaceutical preparations can, for example,be in the form of tablets, dargees, capsules, suppositories, ointmentsor creams or in aliquid form as solutions (for example as an elixir orsyrup), suspensions or emulsions. They are optionally sterilised and/orcontain auxiliaries, such as preservatives, stabilisers, wetting agentsor emulsifiers, or salts for regulating the osmotic pressure or buffers.They can also contain yet other therapeutically valuable substances. Thecompositions, which can also be employed in veterinary medicine, areobtained according to customary methods.

The dosage of the compositions, of the invention depends on the natureof the conditions to be treated and the individual requirements. Forexample, the new compounds mentioned above can be administered orally toa mammal of approximately 75 kg bodyweight in daily dosages of aboutfrom 30 to 300 mg.

The invention also concerns a process for treating tachycardia and/orhypertension wherein a composition referred to above or below isadministered to mammal.

The new compounds can also be used advantageously in pharmaceuticalcompositions in combination with other anti-hypertensive agents and/ordiuretics.

Possible anti-hypertensive compounds are in particular those of the typeof α-amino-β-hydroxyphenyl-propionic acid,β-amino-β-alkoxyphenyl-propionic acid and especially thehydrazinopyridazines and the sympathicolytic agents.

Suitable α-amino-β-hydroxyphenyl-propionic acids are especially thosewhich are lower-alkylated, above all methylated, in the α-position, suchas, above all, α-amino-α-methyl-β-(3,4-dihydroxyphenyl)-propionic acid,optionally in the form of its antipode which is laevo-rotatory inaqueous hydrochloric acid.

Suitable β-amino-α-alkoxyphenyl-propionic acids are especially thosewhich contain lower alkoxy radicals, preferably with up to 6, especiallywith up to 3, C atoms, and especially methoxy groups, in thealkoxyphenyl part, such as, above all,β-amino-β-(3,4-dimethoxyphenyl)-propionic acid, optionally in the formof its dextro-rotatory antipode.

A suitable hydrazinopyridazine is in particular a hydrazinophthalazine,such as 1,4-dihydrazinophthalazine, preferably in the form of one of itssalts, such as of the sulphate, as well as 1-hydrazinophthalazine.

Suitable sympathicolytic agents are especially imidazole derivatives,such as 2-benzyl-4,5-imidazoline, preferably in the form of one of itssalts, such as the hydrochloride, and2-[(N-p-tolyl)-N-(m-hydroxyphenyl)-aminomethyl]-imidazoline, preferablyin the form of one of its salts, such as the hydrochloride ormethanesulphonate.

Suitable sympathicolytic agents are above all anti-hypertonic agentswhich act on the peripheral part of the sympathetic nervous system, suchas sympathetic inhibitors, for exampleN-o-bromobenzyl-N-ethyl-N,N-dimethylammonium p-toluenesulphonate andespecially guanidine derivatives, such as1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, preferably in the formof one of its salts, such as the sulphate,7-bromo-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine, preferably inthe form of one of its salts, such as the sulphate,1-benzyl-2,3-dimethylguanidine, preferably in the form of one of itssalts, such as the sulphate, and above allβ-(1-azacyclooctyl)ethylguanidine, preferably in the form of one of itssalts, such as the sulphate.

Suitable diuretics are substances which increase diuresis both throughrenal and through extra-renal action on the tissues. For this purpose itis possible to use substances having an inhibiting action on thereverse-resorption in the tubulus, such as, for example, in particularsaluretics and ethacrinic acid and its analogues.

Particularly suitable substances are benzothiadiazine derivatives, suchas thiazides and hydrothiazides, benzenesulphonamides, phenoxyaceticacids, benzofurane-2-carboxylic acids andbenzofurane-2,3-dihydro-2-carboxylic acids.

Particularly suitable thiazides are those of the formula XII ##STR8##wherein R₉ is a hydrogen atom or a phenyl-lower alkylthiolower alkyl andR₁₀ is a halogen atom or the trifluoromethyl group.

A phenyl-lower alkylthio-lower alkyl radical R₉ is especially a radicalwherein the lower alkyl parts have up to 4 C atoms and especially 1 Catom and wherein the phenyl part is unsubstituted, such as thebenzyl-thiomethyl radical.

A halogen atom R₁₀ is a bromine atom, iodine atom or fluorine atom orespecially a chlorine atom.

Amongst these compounds of the formula XII there should above all bementioned 6-chloro-7-sulphamyl-1,2,4-benzothiadiazine-1,1-dioxide,6-trifluoromethyl-7-sulphamyl1,2,4-benzothiadiazine-1,1-dioxide and2-benzylthiomethyl-6-chloro-7-sulphamyl-1,2,4-benzothiadiazine-1,1-dioxide.

Particularly suitable hydrothiazides are those of the formula XIII##STR9## wherein R₁₁ is hydrogen or lower alkyl, R₁₂ is hydrogen, loweralkyl, lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl,aryl, aryl-lower alkyl, halogeno-lower alkyl, lower alkylthio-loweralkyl, lower alkenylthio-lower alkyl, halogeno-lower alkylthio-loweralkyl, phenyl-lower alkylthio-lower alkyl or heterocycloalkyl-loweralkyl, R₁₃ is hydrogen or together with R₁₂ represents lower alkyleneand R₁₄ is halogen or trifluoromethyl.

A lower alkyl radical R₁₁ is especially a radical with up to 7 C atoms,above all with up to 4 C atoms, such as ethyl, n-propyl, i-propyl,straight or branched butyl, pentyl, hexyl or heptyl bonded in anydesired position, and above all methyl.

A lower alkyl radical R₁₂ is especially a radical as indicated for R₁₁and above all methyl, ethyl or isobutyl.

A lower alkenyl radical R₁₂ is especially a radical with up to 7,especially up to 4, C atoms, such as allyl.

A cycloalkyl radical R₁₂ is especially a radical with 3-8, above all 5-7, ring C atoms and a total of preferably up to 8, especially up to 7, Catoms, such as cyclopentyl and cyclohexyl.

A cycloalkenyl radical R₁₂ is especially a radical with 5-7, above all5-7, ring C atoms and a total of preferably up to 8 and especially up to7 C atoms, such as cyclopentenyl, cyclohexenyl or norbornenyl,especially 5-norbornen-2-yl.

A cycloalkyl-lower alkyl radical R₁₂ is especially a radical wherein thecycloalkyl part and the lower alkyl part have the above meaning, aboveall cyclopentylmethyl.

An aryl radical R₁₂ is especially a radical with 6 carbon atoms, such asphenyl, which can be substituted by lower alkyl, such as methyl, loweralkoxy, such as methoxy, halogen, such as chlorine, or trifluoromethyl.

An aryl-lower alkyl radical R₁₂ is especially a radical wherein thelower alkyl part has the above meaning and the aryl part is phenylsubstituted by lower alkyl, such as methyl, lower alkoxy, such asmethoxy, halogen, such as chlorine, or trifluoromethyl, or is inparticular unsubstituted phenyl, such as benzyl or 1-phenylethyl.

A halogeno-lower alkyl radical R₁₂ is especially a lower alkyl radicalcarrying one, two or three halogen atoms, wherein the lower alkyl partin particular has the above meaning, such as, in particular,halogenomethyl, for example trifluoromethyl, chloromethyl,dichloromethyl and trichloromethyl.

A lower alkylthio-lower alkyl radical R₁₂ is especially a radicalwherein the lower alkyl part and the lower alkyl part of the loweralkylthio part have the meanings given for lower alkyl above, such asmethylthiomethyl and 2-methylthioethyl.

A lower alkenylthio-lower alkyl radical R₁₂ contains, for example, oneof the abovementioned lower alkenyl radicals and is, for example,allylthiomethyl.

A halogeno-lower alkylthio-lower alkyl radical R₁₂ is in particular aradical as indicated for the lower alkylthio-lower alkyl radical R₁₂which carries one, two or three halogen atoms, such as2,2,2-trifluoroethylthiomethyl.

A phenyl-lower alkylthio-lower alkyl radical R₁₂ is in particular aradical wherein the lower alkyl parts have the above meaning, such asbenzylthiomethyl.

A heterocycloalkyl-lower alkyl radical is, for example, a radical withone or more hetero-atoms in a 3-membered to 10-membered ring, especiallya 5-membered ring, such as, for example, a furyl radical or a pyrrolylradical, and with a lower alkyl part which has up to 7 C atoms, aboveall up to 4 C atoms, such as ethyl, n-propyl, straight or branchedbutyl, pentyl, hexyl or heptyl bonded in any desired position, and aboveall methyl.

A lower alkylene radical formed by R₁₂ and R₁₃ together is especially alower alkylene radical with up to 7, above all with up to 6, C atoms,and especially with at least 2, and in particular with at least 4, Catoms in the alkylene chain, such as 1,5-pentylene and3-methyl-1,5-pentylene.

A halogen atom R₁₄ is bromine, iodine or fluorine and especiallychlorine.

Amongst these compounds of the formula XIII there should above all bementioned:3-Ethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;3-trichloromethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;3-benzyl-6-trifluoromethyl-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;2-methyl-3-(2,2,2-trifluoroethylthiomethyl)-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;3-(2,2,2-trifluoroethylthiomethyl)-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;3-(5-norbornen-2-yl)-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;2-methyl-3-chloromethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;3-dichloromethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;3-cyclopentylmethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;6-trifluoromethyl-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxideand3-isobutyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

Particularly suitable benzenesulphonamides are those of the formula XIV##STR10## wherein R₁₅ is halogen, lower alkyl or trifluoromethyl, R₁₆ ishydrogen, lower alkyl, phenyl-lower alkyl, phenyl which is optionallysubstituted, for example by lower alkoxy or amino, or pyrrolidinomethyl,piperidinomethyl, piperazinomethyl, morpholinomethyl orthiomorpholinomethyl, R₁₇ is carboxyl, carbamoyl, N-mono- orN-di-substituted carbamoyl, sulphamoyl, N-mono- or N-di-substitutedsulphamoyl, lower alkylsulphonyl or isoindolinyl or is joined to theradical R₁₈, R₁₈ is hydrogen, lower alkyl, amino or monosubstituted ordisubstituted amino and R₁₉ is hydrogen or halogen.

A lower alkyl radical R₁₅, R₁₆ or R₁₈ is in particular one of thesementioned above, above all methyl.

An aminophenyl radical R₁₆ is, in particular, a monoaminophenyl radical,such as 4-aminophenyl.

A N-mono-substituted carbamoyl radical R₁₇ is in particular a N-loweralkyl-carbamoyl radical, wherein lower alkyl has the above meaning, suchas the N-methyl-carbamoyl radical, or a N-amino-substituted carbamoylradical, wherein the amino group is in particular di-lower alkylamino,such as dimethylamino, or lower alkylideneamino, such as pyrrolidino,piperidino or 2,6-dimethylpiperidino, such as, for example, theN-(2,6-dimethylpiperidino)-carbamoyl radical.

A N-di-substituted carbamoyl radical R₁₇ is, in particular, a N-di-loweralkylcarbamoyl radical, wherein lower alkyl has the above meanings, suchas the N,N-dimethylcarbamoyl radical.

A N-monosubstituted sulphamoyl radical R₁₇ is in particular a N-loweralkyl-sulphamoyl radical, wherein lower alkyl has the above meaning,such as N-methyl-sulphamoyl, a N-furfuryl- orN-tetrahydrofurfuryl-sulphamoyl radical, such as N-furfuryl-sulphamoyl,N-tetrahydrofurfuryl-sulphamoyl,N-(2-methyl-tetrahydrofurfuryl)-sulphamoyl andN-(2-methyl-4-oxo-tetrahydrofurfuryl)-sulphamoyl.

A N-disubstituted sulphamoyl radical R₁₇ is in particular a N,N-di-loweralkylsulphamoyl radical, wherein lower alkyl has the above meaning, suchas N,N-dimethyl-sulphamoyl, a N,N-lower alkylene-sulphamoyl radical,wherein lower alkylene in particular has the above meaning, such aspiperidino-sulphonyl, a N-lower alkyl-N-carboxy-lower alkyl-sulphamoylradical, wherein the lower alkyl parts have the above meaning, such asN-methyl-N-carboxy-methyl-sulphamoyl, a N-loweralkyl-N-furfuryl-sulphamoyl radical, wherein lower alkyl has the abovemeaning, such as N-methyl-N-furfuryl-sulphamoyl, or a N-loweralkyl-N-tetrahydrofurfuryl-sulphamoyl radical, wherein lower alkyl hasthe above meanings, such asN-methyl-N-(2-methyltetrahydrofurfuryl)-sulphamoyl andN-methyl-N-(2-methyl-4-oxo-tetrahydrofurfuryl)-sulphamoyl.

A lower alkylsulphonyl radical R₁₇ is in particular a radical whereinthe lower alkyl part has the above meaning, such as methylsulphonyl,ethylsulphonyl and n-butylsulphonyl.

An isoindolinyl radical R₁₇ is in particular a 1-isoindolinyl radicalhaving a 3-hydroxy group and a 1-oxo group, such as3-hydroxy-1-oxo-isoindolinyl-(3).

Radicals R₁₇ joined to the radical R₁₈ are especially carbamoyl radicalsR₁₇ which are joined to an amino group R₁₈ or a lower alkyl group R₁₈,such as 1-oxo-2-cyclohexyl-2-azapropylene-(1,3) and1-oxo-2,4-bis-aza-3-ethyl-butylene-(1,4).

A monosubstituted amino group R₁₈ is in particular a lower alkylaminogroup, wherein lower alkyl has the above meaning, such as methylamino,or tetrahydrofurfurylamino or especially furfurylamino or benzylamino.

A disubstituted amino group R₁₈ is especially a di-lower alkylaminogroup, wherein lower alkyl has the above meaning, such as dimethylamino,or a di-(phenyl-lower alkyl)-amino group, wherein the lower alkyl parthas the above meaning, such as dibenzylamino.

A halogen atom R₁₉ is bromine, iodine, fluorine or especially chlorine.

Amongst the compounds of the formula XIV there should especially besingled out those wherein R₁₅ is chlorine, R₁₆ is aminophenyl, methyl orespecially hydrogen, R₁₇ is carboxyl, carbamoyl, N-methyl-carbamoyl,N-(2,6-dimethyl-piperidino)carbamoyl, 3-hydroxy-1-oxo-isoindolinyl-(3)or N-methyl-N-(2-methyl-tetrahydro-furfuryl)-sulphamoyl or together withR₁₈ represents 1-oxo-2-cyclohexyl-2-aza-propylene-(1,3) or1-oxo-2,4-bis-aza-3-ethyl-butylene-(1,4), R₁₈ is hydrogen orfurfurylamino and R₁₉ is hydrogen.

Amongst these compounds of the formula XIV there should in particular bementioned 2-chloro-5-N-methylsulphonamido-benzenesulphonamide;2-chloro-5-N,N-dimethylsulphonamido-benzenesulphonamide;2-chloro-5-piperidinosulphonyl-benzenesulphonamide;2-chloro-5-(N-carboxy-methyl-N-methyl)-sulphonamido-benzenesulphonamide;2-chloro-5-(N-furfuryl-sulphonamido)-benzenesulphonamide;2-chloro-5-(N-tetrahydrofurfuryl-sulphonamido)-benzenesulphonamide;2-chloro-5-[N-methyl-N-(2-methyl-4-oxo-tetrahydrofurfuryl)-sulphonamido]-benzenesulphonamide;4,5-dichlorobenzene-1,3-disulphonamide;4-chloro-6-methylbenzene-1,3-disulphonamide,4-chloro-6-methylbenzene-1,3-disulphonamide,2-chloro-5-methylsulphonylbenzenesulphonamide;2-chloro-5-ethylsulphonyl-benzenesulphonamide;2-chloro-5-n-butylsulphonyl-benzenesulphonamide;2-methyl-5-ethylsulphonyl-benzenesulphonamide;2-methyl-5-methylsulphonyl-benzenesulphonamide;2-methyl-5-n-butylsulphonyl-benzenesulphonamide;2-chloro-4-(N,N-dibenzylamino)-5-carboxyl-benzenesulphonamide;2-furfurylamino-4-chloro-5-N(p-aminophenyl)-sulphamoyl-benzoic acid,2-furfurylamino-4-chloro-5-N(o-aminophenyl)-sulphamoyl-benzoic acid andespecially 3-sulphonamido-4-chloro-benzoic acid;3-sulphonamido-4-chloro-benzamide;3-(N-methylsulphamoyl)-4-chloro-N-methylbenzamide;1-chloro-4-[N-methyl-N-(2-methyltetrahydrofurfuryl)-sulphamoyl]benzenesulphonamide;1,3-disulphamoyl-4-chlorobenzene;2-chloro-5-[3-hydroxy-1-oxo-isoindolinyl-(3)]-benzenesulphonamide;2-ethyl-4-oxo-6-sulphamoyl-7-chloro-1,2,3,4-tetrahydro-quinazoline;1-oxo-2-cyclohexyl-5-chloro-6-sulphamoyl-1,2-dihydro-isoindole;2-chloro-5-[N-(2,6-dimethylpiperidino)-carbamoyl]-benzenesulphonamide;2-chloro-4-furfurylamino-5-carboxyl-benzenesulphonamide and2-chloro-4-benzylamino-5-carboxyl-benzenesulphonamide.

Particularly suitable phenoxyacetic acids are those of the formula XV##STR11## wherein R₂₀ is lower alkyl, R₂₁ is halogen or lower alkyl andR₂₂ is hydrogen, halogen or lower alkyl or wherein R₂₁ and R₂₂ togetherrepresent but-1,3-dienylene-(1,4).

A lower alkyl radical R₂₀ is, in particular, a radical with 2-7, aboveall 2-4, C atoms, such as one of the abovementioned radicals, andpreferably an unbranched radical of this type, such as n-propyl, n-butyland especially ethyl.

A halogen atom R₂₁ or R₂₂ is bromine, iodine or fluorine and especiallychlorine.

A lower alkyl radical R₂₁ or R₂₂ is especially a radical with up to 7,above all up to 4, C atoms, such as, in particular, methyl.

As suitable compounds of the formula XV there should in particular bementioned [2,3-dimethyl-4-(2-methylene-butyryl)-phenoxy]-acetic acid,[2-methyl-3-chloro-4-(2-methylenebutyryl)-phenoxy]-acetic acid,[4-(2-methylene-butyryl)-1-naphthoxy]-acetic acid and especially[2,3-dichloro-4-(2-methylene-butyryl)-phenoxy]-acetic acid.

Particularly suitable benzofurane-2-carboxylic acids are those of theformula XVI ##STR12## wherein R₂₃ is lower alkyl and R₂₄ is lower alkylor lower alkoxy.

A lower alkyl radical R₂₃ is especially a radical with 2-7, above all2-4, C atoms, such as one of those mentioned above, and preferably anunbranched radical of this type, such as ethyl.

A lower alkyl radical R₂₄ is especially a radical with up to 7, aboveall with up to 4, C atoms, such as mentioned above, and in particularmethyl.

A lower alkoxy radical R₂₄ is especially a radical wherein the alkylpart has the above meaning, such as methoxy.

As suitable compounds of the formula XVI there should in particular bementioned 5-(2-methylene-butyryl)-6-methylbenzofurane-2-carboxylic acid,5-(2-methylene-butyryl)-6-methoxy-benzofurane-2-carboxylic acid and5-(2-methylenepropionyl)-6-methyl-benzofurane-2-carboxylic acid.

Particularly suitable benzofurane-2,3-dihydro-2-carboxylic acids arethose of the formula XVII ##STR13## wherein R₂₅ is hydroxyl, alkoxy,cycloalkoxy or arylalkoxy, R₂₆ represents two hydrogen atoms or is loweralkylidene, R₂₇ is lower alkyl, R₂₈ is hydrogen, halogen, lower alkyl orlower alkoxy and R₂₉ is hydrogen or lower alkyl.

An alkoxy radical R₂₅ is especially a radical with 1-18, especially1-12, C atoms, such as one of those mentioned above, such as, inparticular, methoxy, ethoxy, n-butoxy, 2-hexyloxy and n-decyloxy.

A cycloalkoxy radical R₂₅ is especially a radical with 3-8, especially5-7, ring C atoms and especially with up to 10, above all up to 8, Catoms, such as cyclopentyloxy and cyclohexyloxy.

An arylalkoxy radical R₂₅ is especially phenyl-lower alkoxy, wherein thelower alkyl part has the above meaning, such as benzyloxy.

A lower alkylidene radical R₂₆ is especially a radical with up to 7,especially up to 4, C atoms, such as methylene and ethylidene.

A lower alkyl radical R₂₇ is especially a radical with up to 7,especially up to 4, C atoms, such as, in particular, straight-chainradicals of this type, such as methyl, n-propyl, n-butyl and especiallyethyl.

A halogen atom R₂₈ is bromine or iodine and especially fluorine or veryparticularly chlorine.

A lower alkyl radical R₂₈ or R₂₉ is especially a radical with up to 7,in particular with up to 4, C atoms, such as one of those mentionedabove, and above all methyl.

A lower alkoxy radical R₂₈ is especially a radical with up to 7, inparticular with up to 4, C atoms, such as one of those mentioned above,and above all methoxy.

Amongst the compounds of the formula XVII, those wherein R₂₅ ishydroxyl, R₂₆ is methylene or ethylidene, R₂₇ is straight-chain alkylwith 1-4 C atoms, R₂₈ is methyl, methoxy, chlorine or fluorine and R₂₉is hydrogen or methyl, are particularly suitable.

Amongst the compounds of the formula XVII there should be singled out5-(2-methylene-butyryl)-6-methyl-2,3-dihydrobenzofurane-2-carboxylicacid;5-(2-methylene-butyryl)-6-fluoro-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylene-butyryl)-6-chloro-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylene-propionyl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylene-hexanoyl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylene-valeryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylenepropionyl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-ethylidene-butyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid ethyl ester;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid n-butyl ester;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid 2-hexyl ester;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid n-decyl ester;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid cyclopentyl ester;5-(2-methylenebutyryl)-6-methyl)-2,3-dihydro-benzofurane-2-carboxylicacid cyclohexyl ester;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid benzyl ester;5-(2-methylenebutyryl)-7-methyl-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester;5-(2-methylenebutyryl)-6-chloro-7-methyl-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester;5-(2-methylenepropionyl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester;5-(2-methylene-valeryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester;5-(2-methylene-3-methyl-butyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester and5-(2-methylenebutyryl)-6-fluoro-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester and particularly5-(2-methylenebutyryl)-6,7-dimethyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylene-3-methyl-butyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid and5-(2-methylenebutyryl)-6-chloro-7-methyl-2,3-dihydro-benzofurane-2-carboxylicacid.

Particularly valuable pharmaceutical preparations are those whichcontain a compound of the formula Ig in which R', R", R'" and alk' havethe meanings given, above all1-[3-(o-chlorophenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidine,1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(3-methyl-2-oxo-1-imidazolidinyl)-piperidine,1-[3-o-chlorophenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidineor particularly1-[3-(o-methylphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,1-[3-(o-methylphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidineand especially1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidine,together with 1,4-dihydrazinophthalazine sulphate,2-benzyl-4,5-imidazoline hydrochloride,2-[N-p-tolyl)-N-(m-oxyphenyl)-aminomethyl]-imidazoline hydrochloride,1,2,3,4-tetrahydroisoquinoline-2-carboxamidine sulphate or especiallytogether with 1-α-amino-α-methyl-β-(3,4-dihydroxyphenyl)-propionic acidor β-(1-azacyclooctyl)-ethylguanidine sulphate.

Very particularly valuable pharmaceutical preparations are those whichcontain1-[3-(o-chlorophenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidine,1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(3-methyl-2-oxo-1-imidazolidinyl)-piperidine,1-[3-(o-chlorophenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidineor particularly1-[3-(o-methylphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,1-[3-(o-methylphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidineand especially1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidine,together with 1-α-amino-α-methyl-β-(3,4-dihydroxyphenyl)-propionic acidor with β-(1-azacyclooctyl)-ethylguanidine sulphate.

Pharmaceutical preparations of very particular value are those whichcontain1-{1-[3-(o-methoxy-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)together with 1-α-amino-α-methyl-β-(3,4-dihydroxyphenyl)-propionic acidor β-(1-azacyclooctyl)-ethylguanidine sulphate.

Amongst the pharmaceutical preparations which contain a compound of theformula I together with a diuretic, the following are particularlyvaluable:

Preparations which contain a compound of the formula Ig in which R', R",R'" and alk' have the meanings given, above all1-[3-(o-chlorophenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl-piperidine,1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(3-methyl-2-oxo-1-imidazolidinyl)-piperidine,1-[3-(o-chlorophenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidineor particularly1-[3-(o-methylphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,1-[3-(o-methylphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidineand especially1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidine,together with 6-chloro-7-sulphamyl-1,2,4-benzothiadiazine-1,1-diioxide,6-trifluoromethyl-7-sulphamyl-1,2,4-benzothiadiazine-1,1-dioxide and2-benzylthiomethyl-6-chloro-7-sulphamyl-1,2,4-benzothiadiazine-1,1-dioxideor together with3-ethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,3-trichloromethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,3-benzyl-6-trifluoromethyl-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,2-methyl-3-(2,2,2-trifluoroethylthiomethyl)-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,3-(2,2,2-trifluoroethylthiomethyl)-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,3-(5-norbornen-2-yl)-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,2-methyl-3-chloromethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,3-dichloromethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,3-cyclopentylmethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,6-trifluoromethyl-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide or3-isobutyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide or together with 2-chloro-5-N-methyl-sulphonamido-benzenesulphonamide;2-chloro-5-N,N-dimethylsulphonamido-benzenesulphonamide;2-chloro-5-piperidinosulphonyl-benzenesulphonamide;2-chloro-5-(N-carboxy-methyl-N-methyl)-sulphonamide-benzenesulphonamide;2-chloro-5-(N-furfuryl-sulphonamido)-benzenesulphonamide;2-chloro-5-(N-tetrahydrofurfuryl-sulphonamido)-benzenesulphonamide;2-chloro-5-[N-methyl-N-(2-methyl-4-oxo-tetrahydrofurfuryl)-sulphonamido]-benzenesulphonamide;4,5-dichlorobenzene-1,3-disulphonamide;4-chloro-6-methylbenzene-1,3-disulphonamide;4-chloro-6-aminobenzene-1,3-disulphonamide;2-chloro-5-methylsulphonyl-benzenesulphonamide;2-chloro-5-ethylsulphonyl-benzenesulphonamide;2-chloro-5-n-butylsulphonyl-benzenesulphonamide;2-methyl-5-ethylsulphonyl-benzenesulphonamide;2-methyl-5-methylsulphonyl-benzenesulphonamide;2-methyl-5-n-butylsulphonyl-benzenesulphonamide;2-chloro-4-(N,N-dibenzylamino)-5-carboxyl-benzenesulphonamide;2-furfuryl-amino-4-chloro-5-N(p-aminophenyl)-sulphamoyl-benzoic acid,2-furfurylamino-4-chloro-5-N(o-aminophenyl)-sulphamoylbenzoic acid andparticularly 3-sulphonamido-4-chloro-benzoic acid;3-sulphonamide-4-chloro-benzamide;3-(N-methylsulphamoyl)-4-chloro-N-methyl-benzamide;1-chloro-4-[N-(2-methyltetrahydrofurfuryl)-sulphamoyl]benzenesulphonamide;1,3-disulphamoyl-4-chlorobenzene;2-chloro-5-[3-hydroxy-1-oxo-isoindolyl-(3)]-benzenesulphonamide;2-ethyl-4-oxo-6-sulphamoyl-7-chloro-1,2,3,4-tetrahydro-quinazoline;1-oxo-2-cyclohexyl-5-chloro-6-sulphamoyl-1,2-dihydroisoindole;2-chloro-5-[N-(2,6-dimethylpiperidino)-carbamoyl]-benzenesulphonamide;2-chloro-4-furfurylamino-5-carboxyl-benzenesulphonamide and2-chloro-4-benzylamino-5-carboxyl-benzenesulphonamide or together with[2,3-dimethyl-4-(2-methylenebutyryl)-phenoxy]-acetic acid,[2-methyl-3-chloro-4-(2-methylene-butyryl)-phenoxy]-acetic acid,[4-(2-methylenebutyryl)-1-naphthoxy]-acetic acid or[2,3-dichloro-4-(2-methylene-butyryl)-phenoxy]-acetic acid or togetherwith 5-(2-methylene-butyryl)-6-methyl-benzofurane-2-carboxylic acid,5-(2-methylene-butyryl)-6-methoxy-benzofurane-2-carboxylic acid or5-(2-methylene-propionyl)-6-methyl-benzofurane-2-carboxylic acid ortogether with5-(2-methylene-butyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylene-butyryl)-6-fluoro-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylene-butyryl)-6-chloro-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylene-propionyl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylene-hexanoyl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylene-valeryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylenepropionyl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-ethylidene-butyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid ethyl ester;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid n-butyl ester;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid 2-hexyl ester;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid n-decyl ester;5-(2-methylene-butyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid cyclopentyl ester; 5-(2-methylenebutyryl)-6-methyl)-2,3-dihydro-benzofurane-2-carboxylic acidcyclohexyl ester;5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid benzyl ester;5-(2-methylenebutyryl)-7-methyl-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester;5-(2-methylenebutyryl)-6-chloro-7-methyl-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester;5-(2-methylenepropionyl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester;5-(2-methylene-valeryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester; 5-(2-methylene-3-methyl-butyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylic acidmethyl ester; and5-(2-methylenebutyryl)-6-fluoro-2,3-dihydro-benzofurane-2-carboxylicacid methyl ester and particularly 5-(2-methylenebutyryl)-6,7-dimethyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylene-3-methyl-butyryl)-6-methyl-2,3-dihydro-benzofurane-2-carboxylicacid;5-(2-methylenebutyryl)-6-chloro-7-methyl-2,3-dihydro-benzofurane-2-carboxylicacid.

Pharmaceutical preparations of particular value are those which contain1-[3-(o-chlorophenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidine,1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(3-methyl-2-oxo-1imidazolidinyl)-piperidine,1-[3-(o-chlorophenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidineor particularly1-[3-(o-methylphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,1-[3-(o-methylphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidineand especially1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidine,together with 6-chloro-7-sulphamyl-1,2,4-benzothiadiazine-1,1-dioxide,6-trifluoromethyl-7-sulphamyl-1,2,4-benzothiadiazine-1,1-dioxide or2-benzylthiomethyl-6-chloro-7-sulphamyl-1,2,4-benzothiadiazine-1,1-dioxideor together with2-methyl-3-chloromethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,3-dichloro-methyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxideor3-isobutyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxideor together with 3-sulphonamido-4-chloro-benzoic acid,3-sulphonamido-4-chloro-benzamide,3-(N-methylsulphamoyl)-4-chloro-N-methylbenzamide,1-chloro4-[N-methyl-N-(2-methyltetrahydrofurfuryl)-sulphamoyl]-benzenesulphonamide,2-chloro-5-[3-hydroxy-1-oxo-isoindolyl-(3)]-benzenesulphonamide,2-ethyl-4-oxo-6-sulphamoyl-7-chloro-1,2,3,4-tetrahydroquinazoline,1-oxo-2-cyclohexyl-5-chloro-6-sulphamoyl-1,2-dihydroisoindole,2-chloro-5-[N-(2,6-dimethylpiperidino)-carbamoyl]-benzenesulphonamide,2-chloro-4-furfurylamino-5-carboxyl-benzenesulphonamide or2-chloro-4-benzylamino-5-carboxyl-benzenesulphonamide, or together with[2,3-dimethyl-4-(2-methylene-butyryl)-phenoxy]-acetic acid,[2-methyl-3-chloro-4-(2-methylene-butyryl)-phenoxy]-acetic acid,[4-(2-methylene-butyryl)-1-naphthoxy]-acetic acid or[2,3-dichloro-4(2-methylene-butyryl)-phenoxy]acetic acid or togetherwith5-(2-methylene-butyryl)-6,7-dimethyl-2,3-dihydro-benzofurane-2-carboxylicacid,5-(2-methylene-3-methyl-butyryl)-6-methyl-2,3dihydro-benzofurane-2-carboxylicacid or5-(2-methylene-butyryl)-6-chloro-7-methyl-2,3-dihydrobenzofurane-2-carboxylicacid or together with5-(2-methylenebutyryl)-6-methyl-benzofurane-2-carboxylic acid,5-(2-methylene-butyryl)-6-methoxy-benzofurane-2-carboxylic acid or5-(2-methylene-propionyl)- 6-methyl-benzofurane-2-carboxylic acid.

A very particular subject of the invention are pharmaceuticalpreparations which contain1-{1-[3-(o-methoxyphenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazlidinone-2)together with1-oxo-3-(3-sulphamyl-4-chloro-phenyl)-3-hydroxyisoindoline,6-chloro7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide,3-cyclopentylmethyl-6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxideor 5-(2-methylenebutyryl)-6-methyl-benzofurane-2-carboxylic acid.

In the pharmaceutical preparations the active ingredients may be intheir free form or in the form of their salts, if any.

The examples which follow explain the invention without, however,limiting it.

EXAMPLE 1

A solution of 10 g of 1-(o-methoxy-phenoxy)-2,3-epoxypropane and 10 g of1-[piperidyl-(4)]-imidazolidinone-(2) in 50 ml of ethanol is warmed to80° C for 4 hours and then evaporated in vacuo. The residue is dissolvedin 100 ml of 2 N hydrochloric acid, the solution is extracted with etherand the aqueous phase is rendered alkaline by adding 10 N sodiumhydroxide solution.1-{1-[3-(o-Methoxy-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}imidazolidinone-(2)separates out and after recrystallisation from ethanol melts at 138° C.The hydrochloride melts at 158°-160° C.

1-[Piperidyl-(4)]-imidazolidinone-(2) used as the starting material canbe manufactured as follows:

55 g of β-chloroethyl isocyanate are added dropwise to a solution of 47g of 4-aminopyridine in 200 ml of dimethylformamide and the mixture isstirred for 1 hour. On adding 400 ml of water,N-(4-pyridyl)-N'-β-chloroethylurea precipitates and afterrecrystallisation from alcohol-water melts at 120°-122° C.

66 g of N-(4-pyridyl)-N'-β-chloroethyl-urea are heated with a solutionof 12 g of sodium ethylate in 400 ml of ethanol under reflux for 2hours. 1-(4-Pyridyl)-imidazolidinone-(2) precipitates, and melts at205°-206° C.

15 g of 1-(4-pyridyl)-imidazolidinone-(2) in 150 ml of alcohol arehydrogenated in the presence of 1.5 g of ruthenium on charcoal (10percent strength) at 150° C and under a pressure of 150 atmospheresgauge pressure. After the absorption of hydrogen has ceased, thecatalyst is filtered off, the filtrate is evaporated to dryness and theresidue is recrystallised from methylene chloride/petroleum ether.1-[Piperidyl-(4)]-imidazolidinone-(2) is obtained in crystals of meltingpoint 154°-158° C.

EXAMPLE 2

15 g of 1-(m-methoxy-phenoxy)-2,3-epoxy-propane and 15 g of1-[piperidyl-(4)]-imidazolidinone-(2) in 30 ml of ethanol are warmed to80° C for 4 hours and the mixture is then evaporated in vacuo. Theresidue is treated with 100 ml of 2 N hydrochloric acid and extractedwith ether. The aqueous layer is then rendered alkaline by adding 10 Nsodium hydroxide solution and is extracted with methylene chloride.After evaporation of the solvent,1-{1-[3-(m-methoxy-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)is obtained as a viscous oil of which the fumarate melts at 192°-193° C.

EXAMPLE 3

A solution of 15 g of 1-(p-allyloxy-phenoxy)-2,3-epoxy-propane and 15 gof 1-[piperidyl-(4)]-imidazolidinone-(2) in 30 ml of alcohol is warmedto 90° C for 4 hours and subsequently evaporated in vacuo. The residueis dissolved in 2 N hydrochloric acid, the solution is extracted withether and 10 N sodium hydroxide solution is added to the aqueous phaseuntil it gives an alkaline reaction. After extraction with methylenechloride and evaporation of the solvent,1-{1-[3-(p-allyloxyphenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)is left; after recrystallisation from ethanol it melts at 132°-3° C. Themethanesulphonate melts at 154°-7° C.

EXAMPLE 4

10 g of1-{1-[3-(p-benzyloxy-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)in 200 ml of methanol are hydrogenated in the presence of 1 g ofpalladium on charcoal (5 percent strength) at room temperature and undernormal pressure. After the hydrogen uptake has ceased, the catalyst isfiltered off and the solvent is evaporated.1-{1-[3-(p-Hydroxy-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)is left; its hydrochloride melts at 238° C.

In analogous manner, the hydrogenation of1-[3-(o-benzyloxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidineyields the1-[3-(o-hydroxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidine,which melts at 183°-185° C.

EXAMPLE 5

Warming 15 g of 1-(p-benzyloxy-phenoxy)-2,3-epoxypropane and 15 g of1-(4-piperidyl)-2-imidazolidinone in 30 ml of ethanol to 80° C andsubsequently evaporating the solvent yields1-{1-[3-(p-benzyloxyphenyl)-2-hydroxy-1-propyl]piperidyl-(4)}-imidazolidinone-(2),which melts at 166° C.

The1-[3-(o-benzyloxy-phenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidinecan be manufactured in analogous manner.

EXAMPLE 6

A mixture of 15 g of 1-(p-acetamino-phenoxy)-2,3-epoxy-propane, 15 g of1-(4-piperidyl)-2 -imidazolidinone and 30 ml of alcohol is warmed to 80°C for 3 hours and then evaporated in vacuo. The residue is dissolved in2 N hydrochloric acid and extracted with ether, and the aqueous phase isthen rendered alkaline by adding 10 N sodium hydroxide solution.1-{1-[3-(p-Acetamido-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)precipitates and after recrystallisation from ethanol melts at 162°-165°C. The hydrochloride melts at 257°-259° C.

EXAMPLE 7

A mixture of 15 g of 1-(o-allyl-phenoxy)-2,3-epoxy-propane, 15 g of1-(4-piperidyl)-2-imidazolidinone and 30 ml of alcohol is warmed to 80°C for 4 hours and subsequently evaporated. The residue is dissolved in200 ml of 2 N hydrochloric acid and extracted with ether, and theaqueous phase is then rendered alkaline by adding 10 N sodium hydroxidesolution.1-{1-[3-(o-Allyl-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)separates out as an oil. The hydrochloride melts at 186°-189° C.

EXAMPLE 8

A mixture of 15 g of 1-(o-allyloxy-phenoxy)-2,3epoxy-propane, 15 g of1-(4-piperidyl)-2-imidazolidinone and 45 ml of ethanol is warmed to 90°C for 4 hours and then evaporated in vacuo. The residue is dissolved in200 ml of 2 N hydrochloric acid, the solution is extracted with etherand the aqueous phase is then rendered alkaline by adding concentratedsodium hydroxide solution. The1-{1-[3-(o-allyloxyphenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)which has precipitated is extracted by shaking with methylene chloride.The oil which remains after drying and evaporating the methylenechloride is dissolved in 44 ml of ethanol. After adding 10.5 g ofcyclohexylsulphamic acid, crystals of the cyclohexylsulphamate separateout; these melt at 128°-130° C after recrystallisation from ethanol.

EXAMPLE 9

A solution of 30 g of 1-(o-methoxy-phenoxy)-2,3-epoxypropane and 30 g of1-[piperidyl-(4)]-3-methyl-imidazolidinone in 100 ml of ethanol iswarmed to 90° C for 3 hours and evaporated in vacuo. The residue isdissolved in 100 ml of 2 N hydrochloric acid, the solution is extractedwith ether and the aqueous phase is rendered alkaline by adding 10 Nsodium hydroxide solution. After extraction with methylene chloride andevaporation of the solvent,1-{1-[3-(o-methoxy-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-3-methyl-imidazlidinone-(2)remains as an oil. After recrystallisation from ethanol/ether, thehydrochloride melts at 172° C.

1-[Piperidyl-(4)]-3-methyl-imidazolidinone, required as the startingmaterial, can be manufactured by hydrogenation of1-(4-pyridyl)-3-methyl-imidazolidinone-(2) with ruthenium as thecatalyst. The compound melts at 60°-64° C.

EXAMPLE 10

Analogously to the description in Example 1,1-(p-N-methylcarbamoyl-phenoxy)- 2,3-epoxy-propane and1-[piperidyl(4)]-imidazolidinone-(2) yield1-{1-[3-(p-N-methylcarbamoylphenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2),which after recrystallisation from ethyl acetate melts at 180°-182° C,and of which the neutral fumarate, after recrystallisation frommethanol/ether melts at 194°-196° C.

EXAMPLE 11

Analogously to the description in Example 1,1-(o-methyl-phenoxy)-2,3-epoxy-propane and1-[piperidyl-(4)]-imidazolidinone-(2) yield1-{1-[3-(o-methyl-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)of melting point 114°-116° C.

EXAMPLE 12

Analogously to the description in Example 1,1-(o-chloro-phenoxy)-2,3-epoxy-propane and1-[piperidyl-(4)]-imidazolidinone-(2) yield1-{1-[3-(o-chloro-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)of melting point 150°-151° C, of which the neutral fumarate, whenrecrystallised from methanol/ether, melts at 172°-173° C (sintering from170° C onwards).

EXAMPLE 13

Analogously to the description in Example 1,1-(2-methoxy-4-N-methylcarbamoyl-phenoxy)-2,3-epoxy-propane and1-]piperidyl-(4)]-imidazolidinone-(2) yield1-{1-[3-(2-methoxy-4-N-methylcarbamoyl-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)which after recrystallisation from isopropanol melts at 104°-107° C.

EXAMPLE 14

A solution of 6.56 g of 1-(o-tolyloxy)-2,3-epoxy-propane and 7.7 g of1-[piperidyl-(4)]-2-oxo-hexahydro-pyrimidine in 5 ml of ethanol isheated of 3 1/2 hours at a bath temperature of 95° C and then evaporatedin vacuo. The residue is triturated with ethyl acetate, whereuponcrystallisation commences. The crystals are stirred with water andfiltered off. Recrystallisation from ethyl acetate/petroleeum etheryields the1-[3-(o-tolyloxy)-2-hydroxy-propyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidinewhich melts at 145°-147° C.

The 1-[piperidyl-(4)]-2-oxo-hexahydropyrimidine used as startingmaterial can be prepared as follows:

At room temperature, 30 g of γ-chloro-propyl-isocyanate are addeddropwise over the course of 2 hours to a solution of 18.8 g of4-amino-pyridine in 80 ml of dimethyl formamide and stirring iscontinued for 24 hours. After the dimethyl formamide has been evaporatedoff in a water jet vacuum at 80° C, 4.27 g of the residue are dissolvedin 25 ml of methanol and this solution is treated at boiling heat overthe course of 20 minutes with a solution of 1.19 g of sodium methylatein 25 ml of methanol with stirring. The reaction mixture is thenrefluxed for 1 hour. The precipitated sodium chloride is filtered off,the filtrate is evaporated in vacuo and the residue is recrystallisedfrom chloroform/petroleum ether to yield the1-[pyridyl-(4)]-2-oxo-hexahydro-pyrimidine which melts at 180°-182° C.

17.7 g of 1-[pyridyl-(4)]-2-oxo-hexahydro-pyrimidine are hydrogenated in180 ml of water in the presence of 2.5 g of ruthenium on charcoalcatalyst (10%) at 120° C and an atmospheric excess pressure of 120.After the uptake of hydrogen has ceased, thecatalyst is filtered off andthe filtrate is evaporated to dryness. Recrystallisation fromchloroform/petroleum ether yields the1-[piperidyl-(4)]-2-oxo-hexahydro-pyrimidine (m.p. 207°-210° C).

EXAMPLE 15

A solution of 9 g of 1-(o-methoxy-phenoxy)-2,3-epoxypropane and 9.15 gof 1-(4-piperidyl)-2-oxo-hexahydro-pyrimidine in 7 ml of abs. ethanol isheated for 5 hours to 95° C and then evaporated in vacuo. The residue isrecrystallised from ethyl acetate/petroleum ether to yield the1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,which melts at 130°-133° C.

A solution of 17.1 g of the above base in 100 ml of abs. ethanol isadded to a solution of 5.5 g of fumaric acid in 105 ml of abs. ethanol.The1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidinefumarate (1:1) precipitates on the addition of ether; m.p. 149°-151° C.

EXAMPLE 16

A solution of 10.4 g of1-[p-(2-methyoxyethyl)-phenoxy]-2,3-epoxy-propane and 9.15 g of1-(4-piperidyl)-2-oxo-hexahydropyrimidine in 7 ml of abs. ethanol isheated for 5 hours to 95° C and then evaporated in vacuo. The residue isrecrystallised from ethyl acetate/petroleum ether to yield the1-[3-(p-(2-methoxyethyl)-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,which melts at 113°-115° C.

A solution of 18.5 g of the base described above in 30 ml abs. ethanolis added to a solution of 5.5 g of fumaric acid in 105 ml of absoluteethanol. The1-[3-(p-(2-methoxyethyl)-phenoxy)-2-hydroxypropyl]-4-(2-oxohexahydro-1-pyrimidinyl)-piperidinefumarate (2:1) precipitates on the addition of ether; m.p. 157°-159° C.

EXAMPLE 17

A solution of 19.35 g of 1-(p-acetamido-phenoxy)-2,3-epoxy-propane and9.15 g of 1-(4-piperidyl)-2-oxo-hexahydropyrimidine in 10 ml of abs.ethanol is heated to 95° C. The reaction product crystallises out atboiling heat after about 5 minutes. The crystal broth is diluted with 10ml of abs. ethanol and heated for a further 5 hours. When the reactionis terminated the batch is evaporated in vacuo and the residue isrecrystallised from abs. ethanol/ether to yield the1-[3-(p-acetamido-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)piperidine,which melts at 218°-221° C.

EXAMPLE 18

A solution of 9.2 g of 1-(o-chloro-phenoxy)-2,3-epoxypropane and 9.15 gof 1-(4-piperidyl)-2-oxo-hexahydro-pyrimidine in 7 ml of abs. ethanol isheated for 5 hours to 95° C and then evaporated in vacuo. The residue isrecrystallised from chloroform/petroleum ether to yield the1-[3-(o-chloro-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,which melts at 150°-153° C.

A solution of 12.7 g of the above base in 60 ml of abs. ethanol is addedto a solution of 4.05 g of fumaric acid in 77 ml of abs. ethanol. The1-[3-(o-chlorophenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidinefumarate (2:1) precipitates on the addition of ethyl acetate and ether;m.p. 169°-171° C.

EXAMPLE 19

A solution of 10.3 g of 1-(o-allyloxy-phenoxy)-2,3-epoxy-propane and9.15 g of 1-(4-piperidyl)-2-oxo-hexahydropyrimidine in 7 ml abs. ethanolis heated for 5 hours to 95° C and then evaporated in vacuo. The residueis recrystallised from isopropanol to yield the1-[3-(o-allyloxy-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine,which melts at 122°-125° C.

A solution of 8.45 g of the above base in 50 ml of abs. ethanol is addedto a solution of 2.52 g of fumaric acid in 50 ml of abs. ethanol. The1-[3-o-allyloxy-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidinefumarate (1:1) precipitated on addition of ether; m.p. 154°-156° C.

EXAMPLE 20

A solution of 10.8 g of 1-(p-methoxy-phenoxy)-2,3-epoxypropane and 10.15g of 1-(4-piperidyl)-imidazolidin-(2)-one in 10 ml of abs. ethanol isheated for 5 hours to 95° C and then evaporated in vacuo. The residue isdissolved in 80 ml of 2 normal hydrochloric acid. Extraction isperformed with methylene chloride and the aqueous phase is then madealkaline by addition of a concentrated aqueous sodium hydroxidesolution. Extraction with methylene chloride and then evaporation of thesolvent yields the1-[3-(p-methoxy-phenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidine,which melts at 148°-150° C after recrystallisation from isopropanol.

13.7 g of the above base are dissolved in 40 ml of abs. ethanol bywarming. The solution is added to 20.7 ml of a 1.9 N ethanolic solutionof hydrochloric acid. The1-[3-(p-Methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazoidinyl)-piperidinehydrochlorid precipitates on cooling. It melts at 209°-211° C.

EXAMPLE 21

A solution of 0.50 g of1-[3-(o-hydroxy-phenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidinein 20 ml of dimethylformamide is treated with 65 mg of sodium hydridesuspension (55% in paraffin oil) and the mixture is stirred for 1 hourat 20-30° C. Then 0.23 g of methyl iodide is added and the reactionmixture is stirred for 18 hours at 20°-30° C. The solvent is evaporatedoff in vacuo and the residue is then washed with 5 ml of pentane. Theundissolved substance is partitioned between 30 ml of ethyl acetate and3 ml of 6 normal sodium hydroxide solution. The organic phase isextracted once more with 3 ml of 6 normal sodium hydroxide solution,dried over magnesium sulphate and evaporated in vacuo, to yield 0.45 gof a yellow oil. Recrystallisation from ethanol yields pure1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-1-imidazolidinyl)-piperidinewith a melting point of 138° C (melting point of the hydrochloride:158°-160° C). Thin-layer chromatography shows the product to beidentical with that described in Example 1.

EXAMPLE 22

Tablets containing 25 mg of1-{1-[3-(o-methoxy-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)can, for example, be manufactured to have the following composition:

    ______________________________________                                        Composition                                                                   ______________________________________                                        1-{1-[3-(o-Methoxy-phenoxy)-2-hydroxy-]-                                      propyl]-piperidyl(4)}-imidazolidinone-(2)                                                              25.0 mg                                              Lactose                  34.0 mg                                              Wheat starch             30.0 mg                                              Colloidal silica         5.0 mg                                               Talc                     5.0 mg                                               Magnesium stearate       1.0 mg                                                                        100.0                                                ______________________________________                                    

Manufacture

The active compound is mixed with the lactose, the colloidal silica anda part of the wheat starch and the mixture is forcedthrough a sieve. Afurther part of the wheat starch is worked into a paste with a 5-foldamount of water on a water bath and the powder mixture is kneaded withthis paste until a slightly plastic mass has been produced.

The mass is forced through a sieve and dried and the dry granules areagain sieved. Thereafter, the remaining wheat starch, the talc and themagnesium stearate are mixed in and the mixture is pressed to givetablets weighing 100 mg, having a breaking groove.

EXAMPLE 23

Tablets containing 15 mg of1-{1-[3-(o-methoxyphenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)and 10 mg of β-(1-azacyclooctyl)-ethylguanidine sulphate.

    ______________________________________                                        Composition                                                                   ______________________________________                                        1-{1-[3-(o-Methoxy-phenoxy)-2-hydroxy-1-                                      propyl]-piperidyl-(4)}-imidazolidinone-(2)                                                              15.0 mg                                             β-(1-Azacyclooctyl)-ethyl-guanindine sulphate                                                      10.0 mg                                             Lactose                   34.0 mg                                             Wheat starch              30.0 mg                                             Colloidal silica          5.0 mg                                              Talc                      5.0 mg                                              Magnesium stearate        1.0 mg                                                                        100.0 mg                                            ______________________________________                                    

Manufacture

The active compound is mixed with the lactose, the colloidal silica anda part of the wheat starch and the mixture is forced through a sieve. Afurther part of the wheat starch is worked into a paste with a 5-foldamount of water on a water bath and the powder mixture is kneaded withthis paste until a slightly plastic mass has been produced.

The mass is forced through a sieve and dried and the dry granules areagain sieved. Thereafter, the remaining wheat starch, the talc and themagnesium stearate are mixed in and the mixture is pressed to givetablets weighing 100 mg, having a breaking groove.

EXAMPLE 24

Tablets containing 25 mg of1-{1-[3-(o-methoxyphenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-imidazolidinone-(2)and 25 mg of6-chloro-7-sulphamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

    ______________________________________                                        Composition                                                                   ______________________________________                                        1-{1-[3-(o-Methoxy-phenoxy)-2-hydroxy-                                        1-propyl]-piperidyl-(4)}-imidazolidinone-(2)                                                            25.0 mg                                             6-Chloro-7-sulphamyl-3,4-dihydro-1,2,4-                                       benzothiadiazine-1,1-dioxide                                                                            25.0 mg                                             Lactose                   34.0 mg                                             Wheat starch              30.0 mg                                             Colloidal silica          5.0 mg                                              Talc                      5.0 mg                                              Magnesium stearate        1.0 mg                                                                        125.0 mg                                            ______________________________________                                    

Manufacture

The active compound is mixed with the lactose, the colloidal silica anda part of the wheat starch and the mixture of forced through a sieve. Afurther part of the wheat starch is worked into a paste with a 5-foldamount of water on a water bath and the powder mixture is kneaded withthis paste until a slightly plastic mass has been produced.

The mass is forced through a sieve and dried and the dry granules areagain sieved. Thereafter, the remaining wheat starch, the talc and themagnesium stearate are mixed in and the mixture is pressed to givetablets weighing 125 mg, having a breaking groove.

EXAMPLE 25

Tablets containing 25 mg of1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidinecan be manufactured e.g. in the following composition:

    ______________________________________                                        Composition                                                                   ______________________________________                                        1-[3-(o-methoxyphenoxy-2-hydroxypropyl]-                                      4-(2-oxo-hexahydro-1-primidinyl)-kpiperidine                                                            25.0 mg                                             lactose                   34.0 mg                                             wheat starch              30.0 mg                                             colloidal silicic acid    5.0 mg                                              talcum                    5.0 mg                                              magnesium stearate        1.0 mg                                                                        100.0 mg                                            ______________________________________                                    

Manufacture

The active substance is mixed with the lactose, the colloidal silicicacid and a portion of the wheat starch and the mixture is passed througha sieve. A further portion of the wheat starch is pasted on a water bathwith the 5-fold amount of water and the powder mixture is kneaded withthe resulting paste until a slightly plastic mass is obtained. This massif forced through a sieve, dried, and the dry granules are then sieved.The remainder of the wheat starch, the talcum and the magnesium stearateare then admixed and the mixture is pressed into tablets weighing 100 mgwith breaking notch.

EXAMPLE 26

Tablets containing 15 mg of1-[3-(o-tolyloxy)-2-hydroxypropy]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidineand 10 mg of β-(1-azacyclooctyl)-ethyl-guanidine sulphate can bemanufacture e.g. in the following composition:

    ______________________________________                                        Composition                                                                   ______________________________________                                        1-[3-(o-tolyloxy)-2-khydroxypropyl]-4-                                        (2-oxo-hexahydro-1-pyrimidinyl)-piperidine                                                              15.0 mg                                             β-(1-azacyclooctyl)-ethyl-guaniine sulphate                                                        10.0 mg                                             lactose                   34.0 mg                                             wheat starch              30.0 mg                                             colloidal silicic acid    5.0 mg                                              talcum                    5.0 mg                                              magnesium stearate        1.0 mg                                                                        100.0 mg                                            ______________________________________                                    

Tablets weighing 100 mg with breaking notch are manufactured by carryingout the procedure as described in Example 25.

EXAMPLE 27

Tablets containing 25 mg of1-[3-(o-methoxyphenoxy-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidinecan be manufactured e.g. in the following composition:

    ______________________________________                                        Composition                                                                   ______________________________________                                        1-[3-(o-methoxyphenoxy)-2-hydroxy-propyl]-4-                                  (2-oxo-hexahydro-1-pyrimidinyl)-piperidine                                                              25.0 mg                                             6-chloro-7-sulphamyl-3,4-dihydro-1,2,4                                        benzothiadiazine-1,1-dioxide                                                                            25.0 mg                                             lactose                   34.0 mg                                             wheat starch              30.0 mg                                             colloidal silicic acid    5.0 mg                                              talcum                    5.0 mg                                              magnesium stearate        1.0 mg                                                                        125.0 mg                                            ______________________________________                                    

Tablets weighing 125 mg with breaking notch are manufactured by carryingout the procedure as described in Example 25.

We claim:
 1. A piperidine compound having the formula ##STR14## whereinR₁ is phenyl, naphthyl, 5,6,7-tetrahydro-1-naphthyl or5,6,7,8-tetrahydro-2-naphthyl, or phenyl, naphthyl,5,6,7-tetrahydro-1-naphthyl or 5,6,7-tetrahydro-2-naphthyl which aremonosubstituted or disubstituted by lower alkyl, lower alkoxy, loweralkenyl, lower alkenyloxy, halogen, halogen-lower alkyl, carbamoyl,lower alkyl-substituted carbamoyl, lower alkoxycarbonylamino-loweralkyl, lower alkoxy-lower alkoxy, lower alkanoylaminoethenyl, lowerakylthio-lower alkoxy, hydroxyl, lower alkanoyl, lower alkoxy-loweralkyl, lower alkynyl, lower alkylthio-lower alkyl, hydroxy-lower alkyl,lower alkanoyloxy, lower alkylthio, lower alkanoyl amino, cyano, amino,nitro, ureido, lower alkylated ureido, phenyl-lower alkoxy, and/or loweralkynyloxy, R₂ is hydrogen, lower alkyl, lower alkenyl, α-phenyl-loweralkyl or lower alkanoyl, R₃ is hydroxyl, a lower alkanoyloxy or a loweralkoxy, R₄ is hydrogen or lower alkyl, n is an integer from 0 to 4, andalk is trimethylene or mono-lower alkylated trimethylene or atherapeutically acceptable salt thereof.
 2. The compound of claim 1,wherein R₁ is a phenyl or phenyl mono- or di-substituted by lower alkyl,lower alkoxy, lower alkenyl, lower alkenyloxy, lower alkanoyl, loweralkanoylamino, hydroxyl, benzyloxy, N-lower alkylcarbamoyl or halogen,R₂ is hydrogen or lower alkyl, R₃ is hydroxyl, R₄ is hydrogen or methyl,n is 1 and alk is trimethylene or monomethylated trimethylene.
 3. Thecompound of claim 1, wherein R₁ is phenyl monosubstituted by methyl,methoxy, allyl, allyloxy, hydroxyl, acetylamino, propionyl,N-methyl-carbamoyl or chlorine, R₂ is hydrogen, R₃ is hydroxyl, R₄ ishydrogen and alk is trimethylene.
 4. The compound of claim 1, whereinthe compound has the formula ##STR15## in which R' stands for halogen,lower alkyl or lower alkoxy, R" for lower alkyl or hydrogen, R'" formethyl or hydrogen and alk' for trimethylene or a therapeuticallyacceptable salt thereof.
 5. The compounds of claim 1, wherein thecompound has the formula ##STR16## in which R' stands for lower alkyl orlower alkoxy and alk' for trimethylene or a therapeutically acceptablesalt thereof.
 6. A compound as claimed in claim 1, being1-[3-(o-chlorophenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidineor a therapeutically acceptable salt thereof.
 7. A 3as claimed in claim1, being1-[3-(o-methylphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)piperidineor a therapeutically acceptable salt thereof.
 8. A compound as claimedin claim 1, being1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidineor a therapeutically acceptable salt thereof.